The main objectives of this project are to quantify the pathways of catecholamine metabolism in the intact organism (experimental animals and humans) and establish the involvement of disturbances in these pathways in certain disease processes. Tissue, plasma or urine samples are obtained before and during pharmacological or physiological manipulations and analyzed for concentrations of endogenous and exogenous radiolabelled catecholamines and their metabolites. Studies using a recently developed technique for the determination of plasma concentrations of the O~methylated catecholamine metabolites, normetanephrine and metanephrine, have established the relative importance of extraneuronal uptake and metabolism for the inactivation of endogenously released and circulating catecholamines. These studies are being extended to investigations of extra~neuronal catecholamine metabolism and have shown that in the failing heart the contribution of this process to transmitter turnover is reduced whereas the contribution of exocytotic noradrenaline release to turnover is increased. Other clinical studies have indicated that the lungs are a primary source of homovanillic acid, the principal metabolite of dopamine.